ClinVar Genomic variation as it relates to human health
NM_000455.5(STK11):c.1254C>G (p.Cys418Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(11); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000455.5(STK11):c.1254C>G (p.Cys418Trp)
Variation ID: 135918 Accession: VCV000135918.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.3 19: 1226599 (GRCh38) [ NCBI UCSC ] 19: 1226598 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 31, 2016 May 1, 2024 Jan 27, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000455.5:c.1254C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000446.1:p.Cys418Trp missense NC_000019.10:g.1226599C>G NC_000019.9:g.1226598C>G NG_007460.2:g.42193C>G LRG_319:g.42193C>G LRG_319t1:c.1254C>G LRG_319p1:p.Cys418Trp - Protein change
- C418W
- Other names
- p.C418W:TGC>TGG
- p.Cys418Trp
- Canonical SPDI
- NC_000019.10:1226598:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
STK11 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2350 | 2623 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 27, 2024 | RCV000123057.18 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Mar 22, 2023 | RCV000131151.18 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 29, 2022 | RCV000585976.5 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 4, 2022 | RCV002281949.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Uncertain significance
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Peutz-Jeghers syndrome
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002057996.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
|
|
Uncertain significance
(Oct 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004221271.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000073 (6/81688 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for … (more)
The frequency of this variant in the general population, 0.000073 (6/81688 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in an individual undergoing multigene hereditary cancer panel testing (PMID: 26845104 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
Uncertain significance
(May 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224520.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
BP4, PM2
Number of individuals with the variant: 1
|
|
Uncertain significance
(Mar 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000686608.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces cysteine with tryptophan at codon 418 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces cysteine with tryptophan at codon 418 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/195444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Jan 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Peutz-Jeghers syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000166352.12
First in ClinVar: Jun 16, 2014 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 418 of the STK11 … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 418 of the STK11 protein (p.Cys418Trp). This variant is present in population databases (rs587780715, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 135918). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Nov 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266231.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
Number of individuals with the variant: 1
|
|
Uncertain significance
(Aug 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696708.2
First in ClinVar: Mar 17, 2018 Last updated: Sep 17, 2022 |
Comment:
Variant summary: STK11 c.1254C>G (p.Cys418Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: STK11 c.1254C>G (p.Cys418Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 164078 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1254C>G has been reported in the literature in individuals affected with Peutz-Jeghers Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain significance
(Nov 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Peutz-Jeghers syndrome
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000487848.2
First in ClinVar: Jan 31, 2016 Last updated: Dec 24, 2022 |
|
|
Uncertain significance
(Jun 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000211729.15
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual undergoing multigene hereditary cancer panel testing (Shirts 2016); … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual undergoing multigene hereditary cancer panel testing (Shirts 2016); This variant is associated with the following publications: (PMID: 26845104, 27535533, 28900777) (less)
|
|
Uncertain significance
(Apr 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Peutz-Jeghers syndrome
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018018.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
|
|
Uncertain Significance
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Peutz-Jeghers syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004819024.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces cysteine with tryptophan at codon 418 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces cysteine with tryptophan at codon 418 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/195444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 11
|
|
Likely benign
(Nov 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186093.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
Uncertain significance
(Aug 01, 2016)
|
no assertion criteria provided
Method: research
|
Peutz-Jeghers syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: CSER - NEXT Medicine variant annotation
Accession: SCV000503556.1 First in ClinVar: Jan 31, 2016 Last updated: Jan 31, 2016 |
Comment:
Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 47 year old with a history of … (more)
Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 47 year old with a history of colon cancer diagnosed at 47 and a family history of colon cancer. (less)
|
|
click to load more click to collapse |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition. | Lee YR | The New England journal of medicine | 2020 | PMID: 32459922 |
Improving performance of multigene panels for genomic analysis of cancer predisposition. | Shirts BH | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26845104 |
Text-mined citations for rs587780715 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.